Biology subjects

Stevenson, T. J.

Publications and source records attributed to Stevenson, T. J..

6 recordsLinked to original sources

bioRxiv2026

Systematic screening identifies elevated neurovascular BCL-XL in Parkinson's disease.

BackgroundVascular cells are emerging as active players in Parkinsons disease (PD), yet their molecular contribution to -Synuclein (-Syn) pathology remains undefined. Here, we show that human brain pericytes respond in a distinct manner to unique -Syn strains, with systematic validation identifying BCL-XL as a potential regulator of the neurovascular unit in PD. MethodsPrimary human brain-derived pericytes were exposed to five recombinant -Syn strains (Fibrils, Fibrils-65, Fibrils-91, Fibrils-110, and Ribbons). Transcriptomic profiling identified differentially expressed genes (DEGs), which were validated at the protein level using multiplex immunocytochemistry and in situ labelling of post-mortem middle temporal gyrus (MTG) tissue microarrays from PD (n = 24) and neurologically normal (n = 24) cases. Results-Syn strain exposure produced 300 DEGs with limited overlap between strains. BCL-XL and CSNK1D were upregulated in -Syn-treated pericytes. In post-mortem PD tissue BCL-XL showed marked pericyte-specific elevation in the MTG and increased pericytic and microglial expression in the substantia nigra. ConclusionBCL-XL emerges as a potential regulator of pericyte and microglial resilience in PD, linking acute -Syn strain-specific responses in pericytes to broader neurovascular alterations. Its upregulation likely represents a generalised compensatory response to chronic -Syn-associated stress beyond individual strain effects, identifying BCL-XL as a possible therapeutic target within the neurovascular unit.

neuroscience↗

bioRxiv2025

ATAD1 Overexpression Enhances Mitochondrial and Peroxisomal Function in Zellweger Syndrome Disorder Models

Zellweger Spectrum Disorders (ZSDs) are caused by mutations in any of the different peroxin (PEX) genes, which are essential for peroxisome biogenesis and function. Clinical features of ZSDs include seizures, leukodystrophy, renal and liver dysfunction, skeletal abnormalities, and they usually result in death during infancy or early childhood. There are no treatments for ZSDs, and their rarity, the large size of the PEX genes, and the numerous different genes, has impaired therapeutic development. We previously demonstrated that ATAD1, a mitochondrial protein quality control chaperone, could correct both mitochondrial and peroxisomal phenotypes in PEX3 patient fibroblasts. In this study, we investigated whether overexpressing ATAD1 could provide similar benefits in PEX1 and PEX6 patient cell lines, which account for over 70% of ZSD cases. We used established PEX6-/- HEK293 cells, patient-derived fibroblasts with pathogenic PEX1 mutations, and newly created zebrafish mutants. Lipidomic profiling of the cell lines demonstrated widespread dysregulation, including accumulation of lysophosphatidylcholines with very-long-chain fatty acids, depletion of plasmalogens and cholesteryl esters containing polyunsaturated fatty acids, and a decrease in cardiolipins. Overexpressing ATAD1 partly corrected these imbalances, including normalizing VLCFA metabolism in PEX1 fibroblasts and restoring plasmalogens and cardiolipins in PEX6-deficient cells. Mitochondrial function analysis (Seahorse XF) showed that ATAD1 increased basal and ATP-linked respiration in both PEX1- and PEX6-deficient cells, sometimes surpassing the effects of PEX gene re-expression. ATAD1 increased peroxisome numbers in both PEX6 and PEX1 cells. Zebrafish Pex1 mutants exhibited impaired maximal respiration despite normal basal activity, confirming mitochondrial vulnerability in vivo. These findings further confirm a role for ATAD1 as a modifier that improves lipid metabolism, mitochondrial function, and peroxisome abundance that could function across multiple ZSDs.

neuroscience↗

bioRxiv2025

Seasonal neurogenomic changes provide genetic links between male song and testosterone-mediated neurogenesis in a wild songbird

Seasonal changes in testosterone mediate the transition from reduced singing in the non-breeding season to high song rates in the early breeding season in male temperate songbirds, a process accompanied by marked neurogenesis in song control regions of the brain. However, the resulting genetic changes and their association with the subsequent behavioral, neuroanatomical and reproductive changes remain poorly understood. Here, we compared gene expression in HVC, a major song control nucleus, between the non-breeding and breeding season in male northern house wrens (Troglodytes aedon) and we examined associations with HVC volume, plasma testosterone concentrations, and testes size. Differential gene expression analysis identified three genes (CLIP4, FAM169A, and TTR) consistently linked to seasonal transitions from non-breeding to three breeding stages (pre-laying, egg-laying and incubation). Notably, TTR, which transports thyroid hormone (TH), was highly expressed in the nonbreeding season, consistent with a possible role of TH in regulating seasonal shifts in song output and structure. We also identified seasonal changes in networks of genes related to neural connectivity, cellular restructuring, and cell migration. Weighted gene co-expression network analysis (WGCNA) revealed gene clusters specifically correlated with testosterone and HVC volume. Testosterone-associated genes included genes involved in neural circuit remodeling, chromatin organization, and cytoskeletal dynamics, consistent with testosterone-mediated regulation of these neuroanatomical changes. Genes linked to seasonal increases in HVC volume were involved in neuronal restructuring and neuron migration, implicating these genes in seasonal neurogenesis. Together, our findings link novel gene expression patterns to hormone regulation and neurogenesis underlying seasonal transitions in birdsong.

genomics↗

bioRxiv2025

Hypothalamic deiodinase type-3 establishes the period of circannual interval timing in mammals

Animals respond to environmental cues to time phenological events, but the intrinsic mechanism of circannual timing remains elusive. We used transcriptomic sequencing and frequent sampling of multiple hypothalamic nuclei in Djungarian hamster to examine the neural and molecular architecture of circannual interval timing. Our study identified three distinct phases of transcript changes, with deiodinase type-3 (Dio3) expression activated during the early induction phase. Subsequent work demonstrated that targeted mutation of Dio3 using CRISPR-Cas resulted in a shorter period for circannual interval timing. Hamsters that are non-responsive to short photoperiod and fail to show any winter adaptations do not display changes in Dio3 expression do not show any change in body mass or pelage. Our work demonstrates that changes in Dio3 induction is essential for setting the period of circannual interval timing.

neuroscience↗

bioRxiv2022

Human pericytes degrade alpha-synuclein aggregates in a strain-dependent manner

Parkinsons disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of -synuclein (-syn) aggregates. Central to disease progression is the gradual spread of pathological -syn. -syn aggregation is closely linked to progressive neuron loss. As such, clearance of -syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy are increasing. Our previous work has shown that pericytes -- vascular mural cells that regulate the blood-brain barrier -- contain -syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar -syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes efficiently break down -syn aggregates in vitro, with clear differences in the number of -syn aggregates/cell and average aggregate size when comparing five pure -syn strains (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110). Furthermore, pericytes derived from PD brains have a less uniform response than those derived from control brains. Our results highlight the vital role brain vasculature may play in reducing -syn burden in PD.

neuroscience↗

bioRxiv2021

Epigenetic Control of Temperature-Dependent Female Reproductive Life History Trade-Offs in Seed Beetles, Callosobruchus maculatus

Many species are threatened by climate change and must rapidly respond to survive changing environments. Epigenetic modifications, such as DNA methylation, can facilitate plastic responses by regulating gene expression in response to environmental cues. Understanding epigenetic responses is therefore essential for predicting species ability to rapidly adapt in the context of global environmental change. Here, we investigated the functional significance of DNA methylation on temperature-dependent life history in seed beetles, Callosobruchus maculatus. We assessed changes in DNA methyltransferase (Dnmt1 and Dnmt2) expression levels under ambient conditions and thermal stress, and reproductive performance following artificially-induced epimutation via 3-aminobenzamide (3AB) and Zebularine (Zeb), at a range of ambient and warmer temperatures over two generations. We found that Dnmt1 and Dnmt2 were greatly expressed in females, throughout the body, and exhibited temperature-dependence; in contrast, Dnmt expression was minimal in males. Epimutation led to shifts in female reproductive life history trade-off allocation, and differentially altered thermal optima of fecundity and offspring viability. This study revealed the optimal allocation strategy among these fitness components is temperature-dependent, and trade-offs become increasingly difficult to resolve epigenetically under more extreme warming. Results suggest that epigenetic mechanisms are strongly implicated in, and perhaps limiting of, invertebrate life history responses to temperature change. Further investigation will reveal targeted DNA methylation patterns and specific loci associated with temperature-dependent life history trade-offs in seed beetles and other invertebrates.

evolutionary biology↗